Finishing blow therapy in lung cancer with driver gene mutation

• Project/Area Number: 25461172
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Nippon Medical School
• Principal Investigator: Gemma Akihiko 日本医科大学, 医学(系)研究科(研究院), 教授 (20234651)
• Co-Investigator(Kenkyū-buntansha): SEIKE Masahiro 日本医科大学, 医学部, 准教授 (30366687) ; TANAKA Nobuyuki 日本医科大学, 大学院医学研究科, 大学院教授 (80222115)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ドライバー遺伝子 / セカンドアタック / 肺癌 / cancer stem cell / アポトーシス / 転写因子 / driver gene 変異 / p53

Outline of Final Research Achievements

In order to cure lung cancer with driver gene mutation, we searched second targets of the tumors. We focused on the molecules concerning with the cancer stem cell properties in the resistant cell subpopulations after drug exposure and the molecules in p53 signaling. At first, we established five resistant subpopulations with cancer stem cell like properties of lung cancer cell lines with driver gene mutation and identified the key molecules of the resistance. In addition, we identified the transcriptional molecules in PI3K-mTOR signaling varied in the process of EGFR-TKI treatment. Drug induced apotosis was dependent on Bax- and Bak-induction pathway and activated by BH3-mimetic ABT-263.

Research Products

• [Journal Article] Cisplatin-induced apoptosis in non-small-cell lung cancer cells is dependent on Bax- and Bak-induction pathway and synergistically activated by BH3-mimetic ABT-263 in p53 wild-type and mutant cells. (2016)
  • Author(s): Matsumoto M, Nakajima W, Seike M, Gemma A, Tanaka N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 473(2) Issue: 2 Pages: 490-6
  • DOI: 10.1016/j.bbrc.2016.03.053
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of adverse events that have a negative impact on quality of life in a clinical trial comparing docetaxel versus S-1 with cisplatin in lung cancer. (2016)
  • Author(s): Aotani E, Hamano T, Gemma A, Takeuchi M, Takebayashi T, Kobayashi K.
  • Journal Title: Int J Clin Oncol. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells. (2016)
  • Author(s): Nishijima N, Seike M, Soeno C, Chiba M, Miyanaga A, Noro R, Sugano T, Matsumoto M, Kubota K, Gemma A.
  • Journal Title: Int J Oncol. Volume: 48(3) Issue: 3 Pages: 937-44
  • DOI: 10.3892/ijo.2016.3331
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of haptoglobin peptide as a novel serum biomarker for lung squamous cell carcinoma by serum proteome and peptidome profiling. (2016)
  • Author(s): Okano T, Seike M, Kuribayashi H, Soeno C, Ishii T, Kida K, Gemma A.
  • Journal Title: Int J Oncol. Volume: 48(3) Issue: 3 Pages: 945-52
  • DOI: 10.3892/ijo.2016.3330
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma. (2016)
  • Author(s): Hisakane K, Saruwatari K, Fujii S, Kirita K, Umemura S, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Kuwata T, Ochiai A, Gemma A, Tsuboi M, Goto K, Ishii G.
  • Journal Title: J Cancer Res Clin Oncol. Volume: 142(3) Issue: 3 Pages: 593-600
  • DOI: 10.1007/s00432-015-2068-1
  • Peer Reviewed
• [Journal Article] Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer. (2015)
  • Author(s): Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, Nakamichi S, Nishijima N, Matsumoto M, Miyanaga A, Kubota K, Gemma A.
  • Journal Title: Mol Cancer Ther. Volume: 14(11) Issue: 11 Pages: 2433-40
  • DOI: 10.1158/1535-7163.mct-15-0050
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth. (2015)
  • Author(s): Takahashi A, Ishii G, Neri S, Yoshida T, Hashimoto H, Suzuki S, Umemura S, Matsumoto S, Yoh K, Niho S, Goto K, Ohmatsu H, Nagai K, Gemma A, Ohe Y, Ochiai A.
  • Journal Title: Oncotarget. Volume: 6(11) Pages: 9531-41
  • Peer Reviewed
• [Journal Article] A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. (2015)
  • Author(s): Kubota, K., Sakai, H., Katakami, N., Nishio, M., Inoue, A., Okamoto, H., Isobe, H., Kunitoh, H., Takiguchi, Y., Kobayashi, K., Nakamura, Y., Ohmatsu, H., Sugawara, S., Minato, K., Fukuda, M., Yokoyama, A., Takeuchi, M., Michimae, H., Gemma, A. and Kudoh, S.
  • Journal Title: Annals of Oncology Volume: 26 Issue: 7 Pages: 1401-1408
  • DOI: 10.1093/annonc/mdv190
  • Peer Reviewed
• [Journal Article] Hippo Pathway Gene Mutations in Malignant Mesothelioma, Revealed by RNA and Targeted Exon Sequencing (2015)
  • Author(s): Miyanaga A, Masuda M, Tsuta K, Kawasaki K, Nakamura Y, Sakuma T, Asamura H, Gemma A, Yamada T.
  • Journal Title: J Thorac Oncol Volume: 10(5) Issue: 5 Pages: 844-851
  • DOI: 10.1097/jto.0000000000000493
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effective Crizotinib schedule for an elderly patient with ALK rearranged non-small-cell lung cancer: a case report. (2015)
  • Author(s): Fukuizumi A, Miyanaga A, Seike M, Kato Y, Nakamichi S, Chubachi K, Matsumoto M, Noro R, Minegishi Y, Kunugi S, Kubota K, Gemma A
  • Journal Title: BMC Res Notes. Volume: 8 Issue: 1 Pages: 165-165
  • DOI: 10.1186/s13104-015-1126-8
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002) (2015)
  • Author(s): Miyauchi E, Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Saijo Y, Yoshizawa H, Hagiwara K, Nukiwa T; North-East Japan Study Group
  • Journal Title: Jpn J Clin Oncol Volume: 45 Issue: 7 Pages: 670-6
  • DOI: 10.1093/jjco/hyv054
  • Peer Reviewed / Open Access
• [Journal Article] Phase II study of carboplatin, docetaxel and bevacizumab for chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer. (2015)
  • Author(s): Takiguchi, Y., Iwasawa, S., Minato, K., Miura, Y., Gemma, A., Noro, R., Yoshimori, K., Shingyoji, M., Hino, M., Ando, M. and Okamoto, H.
  • Journal Title: Int J Clin Oncol Volume: 20 Issue: 4 Pages: 659-667
  • DOI: 10.1007/s10147-014-0755-6
  • Peer Reviewed
• [Journal Article] MET FISH-positive status predicts short progression-free survival and overall survival after gefitinib treatment in lung adenocarcinoma with EGFR mutation. (2015)
  • Author(s): Noro R, Seike M, Zou F, Soeno C, Matsuda K, Sugano T, Nishijima N, Matsumoto M, Kitamura K, Kosaihira S, Minegishi Y, Yoshimura A, Kubota K, Gemma A.
  • Journal Title: BMC Cancer Volume: 15(1) Pages: 31-31
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Control of the MYC-eIF4E axis plus mTOR inhibitor treatment in small cell lung cancer. (2015)
  • Author(s): Matsumoto M, Seike M, Noro R, Soeno C, Sugano T, Takeuchi S, Miyanaga A, Kitamura K, Kubota K, Gemma A.
  • Journal Title: BMC Cancer Volume: 15(1) Pages: 241-241
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nintedanib modulates surfactant protein-D expression in A549 human lung epithelial cells via the c-Jun N-terminal kinase-activator protein-1 pathway. (2015)
  • Author(s): Kamio K, Usuki J, Azuma A, Matsuda K, Ishii T, Inomata M, Hayashi H, Kokuho N, Fujita K, Saito Y, Miya T, Gemma A.
  • Journal Title: Pulm Pharmacol Ther. Volume: 5539(15) Pages: 00036-00036
  • DOI: 10.1016/j.pupt.2015.03.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Factors associated with a poor response to gefitinib in the NEJ002 study: Smoking and the L858R mutation. (2015)
  • Author(s): Fukuhara T, Yoshizawa H et al.
  • Journal Title: Lung Cancer Volume: 88 Issue: 2 Pages: 181-6
  • DOI: 10.1016/j.lungcan.2015.02.004
  • Peer Reviewed / Open Access
• [Journal Article] Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. (2015)
  • Author(s): Sugawara S, Oizumi S, Minato K, Harada T, Inoue A, Fujita Y, Maemondo M, Yoshizawa H, Ito K, Gemma A, Nishitsuji M, Harada M, Isobe H, Kinoshita I, Morita S, Kobayashi K, Hagiwara K, Kurihara M, Nukiwa T; North East Japan Study Group and Tokyo Cooperative Oncology Group
  • Journal Title: Ann Oncol. Volume: 26(5) Issue: 5 Pages: 888-94
  • DOI: 10.1093/annonc/mdv063
  • Peer Reviewed / Open Access
• [Journal Article] First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies. (2015)
  • Author(s): Morikawa N, Minegishi Y, Inoue A, Maemondo M, Kobayashi K, Sugawara S, Harada M, Hagiwara K, Okinaga S, Oizumi S, Nukiwa T, Gemma A; North-East Japan Study Group.
  • Journal Title: Expert Opin Pharmacother. Volume: 16(4) Issue: 4 Pages: 465-72
  • DOI: 10.1517/14656566.2015.1002396
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of PIK3CA and SOX2 in Asian patients with lung squamous cell carcinoma. (2015)
  • Author(s): Iijima Y, Seike M, Noro R, Ibi T, Takeuchi S, Mikami I, Koizumi K, Usuda J, Gemma A.
  • Journal Title: Int J Oncol. Volume: 46(2) Issue: 2 Pages: 505-12
  • DOI: 10.3892/ijo.2014.2742
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MiR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma. (2015)
  • Author(s): Yamamoto K, Seike M, Takeuchi S, Soeno C, Miyanaga A, Noro R, Minegishi Y, Kubota K, Gemma A.
  • Journal Title: Oncol Rep. Volume: 32(6) Issue: 6 Pages: 2365-72
  • DOI: 10.3892/or.2014.3481
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Final safety and efficacy of erlotinib in the phase 4 POLARSTAR surveillance study of 10 708 Japanese patients with non-small-cell lung cancer. (2014)
  • Author(s): Gemma A, Kudoh S, Ando M, Ohe Y, Nakagawa K, Johkoh T, Yamazaki N, Arakawa H, Inoue Y, Ebina M, Kusumoto M, Kuwano K, Sakai F, Taniguchi H, Fukuda Y, Seki A, Ishii T, Fukuoka M.
  • Journal Title: Cancer Sci. Volume: 105(12) Issue: 12 Pages: 1584-90
  • DOI: 10.1111/cas.12550
  • Peer Reviewed / Open Access
• [Journal Article] A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: Re-evaluation of EGFR gene status (NEJ006/TCOG0903) (2014)
  • Author(s): Matsumoto Y, Maemondo M, Ishii Y, Okudera K, Demura Y, Takamura K, Kobayashi K, Morikawa N, Gemma A, Ishimoto O, Usui K, Harada M, Miura S, Fujita Y, Sato I, Saijo Y;
  • Journal Title: Lung Cancer Volume: 86 Issue: 2 Pages: 195-200
  • DOI: 10.1016/j.lungcan.2014.08.019
  • Peer Reviewed / Open Access
• [Journal Article] Incidence and clinical features of drug-induced lung injury in patients with advanced colorectal cancer receiving cetuximab: results of a prospective multicenter registry. (2014)
  • Author(s): Satoh T, Gemma A, Kudoh S, Sakai F, Yamaguchi K, Watanabe T, Ishiguro M, Inoshiri S, Izawa M, Sugihara K, Sakata Y.
  • Journal Title: Jpn J Clin Oncol. Volume: 44(11) Issue: 11 Pages: 1032-9
  • DOI: 10.1093/jjco/hyu128
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A descriptive analysis of post-chemotherapy development of interstitial lung disease using spontaneous reporting data in Japan. (2014)
  • Author(s): Hirakawa A, Yonemori K, Kuwatsuka Y, Kodaira M, Yamamoto H, Yunokawa M, Hamada A, Shimizu C, Tamura K, Gemma A, Fujiwara Y.
  • Journal Title: Curr Drug Saf. Volume: 9(3) Pages: 220-6
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features, anti-cancer treatments and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema. (2014)
  • Author(s): Minegishi Y, Kokuho N, Miura Y, Matsumoto M, Miyanaga A, Noro R, Saito Y, Seike M, Kubota K, Azuma A, Kida K, Gemma A.
  • Journal Title: Lung Cancer Volume: 85(2) Issue: 2 Pages: 258-63
  • DOI: 10.1016/j.lungcan.2014.05.016
  • Peer Reviewed / Open Access
• [Journal Article] Significance of osteopontin in the sensitivity of malignant pleural mesothelioma to pemetrexed. (2014)
  • Author(s): Takeuchi S, Seike M, Noro R, Soeno C, Sugano T, Zou F, Uesaka H, Nishijima N, Matsumoto M, Minegishi Y, Kubota K, Gemma A.
  • Journal Title: Int J Oncol. Volume: 44(6) Issue: 6 Pages: 1886-94
  • DOI: 10.3892/ijo.2014.2370
  • Peer Reviewed
• [Journal Article] Randomized Phase II Trial Comparing Carboplatin Plus Weekly Paclitaxel and Docetaxel Alone in Elderly Patients With Advanced Non-Small Cell Lung Cancer: North Japan Lung Cancer Group Trial 0801 (2014)
  • Author(s): Maemondo M, Inoue A, Sugawara S, Harada T, Minegishi Y, Usui K, Miwa K, Morikawa N, Kambe M, Ube K, Watanabe K, Ishimoto O, Sakakibara T, Gemma A, Nukiwa T
  • Journal Title: Oncologist Volume: 19 Issue: 4 Pages: 352-353
  • DOI: 10.1634/theoncologist.2013-0411
  • Peer Reviewed
• [Journal Article] Panitumumab in Japanese patients with unresectable colorectal cancer: a post-marketing surveillance study of 3085 patients. (2014)
  • Author(s): Boku N, Sugihara K, Kitagawa Y, Hatake K, Gemma A, Yamazaki N, Muro K, Hamaguchi T, Yoshino T, Yana I, Ueno H, Ohtsu A.
  • Journal Title: Jpn J Clin Oncol Volume: 44(3) Issue: 3 Pages: 214-23
  • DOI: 10.1093/jjco/hyt196
  • Peer Reviewed
• [Journal Article] Nestin regulates proliferation, migration, invasion and stemness of lung adenocarcinoma (2014)
  • Author(s): Narita K, Matsuda Y, Seike M, Naito Z, Gemma A, Ishiwata T
  • Journal Title: Int J Oncol Volume: 44(4) Issue: 4 Pages: 1118-30
  • DOI: 10.3892/ijo.2014.2278
  • Peer Reviewed
• [Journal Article] Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. (2014)
  • Author(s): Watanabe S, Yoshizawa H et al.
  • Journal Title: J Thorac Oncol. Volume: 11 Issue: 2 Pages: 189-94
  • DOI: 10.1097/jto.0000000000000048
  • Peer Reviewed / Open Access
• [Journal Article] Bortezomib therapy-related lung disease in Japanese patients with multiple myeloma: incidence, mortality and clinical characterization. (2014)
  • Author(s): Yoshizawa K, Mukai HY, Miyazawa M, Miyao M, Ogawa Y, Ohyashiki K, Katoh T, Kusumoto M, Gemma A, Sakai F, Sugiyama Y, Hatake K, Fukuda Y, Kudoh S.
  • Journal Title: Cancer Sci. Volume: 105(2) Issue: 2 Pages: 195-201
  • DOI: 10.1111/cas.12335
  • Peer Reviewed
• [Journal Article] MiR-134/487b/655 cluster regulates TGF-β-induced epithelial-mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells (2014)
  • Author(s): Kitakura K, Seike M, Okano T et.al
  • Journal Title: Molecular Cancer Therapeutic Volume: 13(2) Issue: 2 Pages: 444-453
  • DOI: 10.1158/1535-7163.mct-13-0448
  • Peer Reviewed
• [Journal Article] Distinct outcome of stage I lung adenocarcinoma with ACTN4 cell motility gene amplification. (2013)
  • Author(s): Noro R1, Honda K, Tsuta K, Ishii G, Maeshima AM, Miura N, Furuta K, Shibata T, Tsuda H, Ochiai A, Sakuma T, Nishijima N, Gemma A, Asamura H, Nagai K, Yamada T.
  • Journal Title: Ann Oncol Volume: Oct;24(10): Issue: 10 Pages: 2594-600
  • DOI: 10.1093/annonc/mdt293
  • Peer Reviewed
• [Journal Article] Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4-ALK-rearranged non-small-cell lung cancer harbored coexisting EGFR mutation. (2013)
  • Author(s): Miyanaga A, et al. 18人中14番目
  • Journal Title: BMC Cancer Volume: 13 Issue: 1 Pages: 262-262
  • DOI: 10.1186/1471-2407-13-262
  • Peer Reviewed
• [Presentation] 肺癌におけるmicroRNA異常の解明と新規治療法の開発に向けた研究 (2014)
  • Author(s): 清家正博
  • Organizer: 第５５回日本肺癌学会（学会賞受賞講演）
  • Place of Presentation: 京都
  • Year and Date: 2014-11-15
  • Invited
• [Presentation] EMT による耐性 (2014)
  • Author(s): 清家正博
  • Organizer: 第５４回日本呼吸器学会（招請講演）
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-16
  • Invited
• [Presentation] シンポジウム 最近の分子生物学の進歩とがん研究 低分子RNAとがん研究
  • Author(s): 清家正博
  • Organizer: 第５３回日本呼吸器学会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 肺がん治療の最前線 肺癌治療感受性予測研究の展開
  • Author(s): 清家正博
  • Organizer: 第５１回日本癌治療学会
  • Place of Presentation: 京都
  • Invited
• [Book] オンコロジークリニカルガイド「肺癌化学療法」 (2014)
  • Author(s): 弦間昭彦
  • Total Pages: 432
  • Publisher: 南山堂
• [Book] 呼吸器疾患診療 最新ガイドライン (2014)
  • Author(s): 弦間昭彦
  • Total Pages: 395
  • Publisher: 総合医学社
• [Book] 分子標的治療薬マスターガイド (2014)
  • Author(s): 弦間昭彦
  • Total Pages: 255
  • Publisher: 中外医学社
• [Book] 肺癌診療Q＆A (2013)
  • Author(s): 弦間昭彦
  • Total Pages: 421
  • Publisher: 中外出版社